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A Clinical Trial Evaluating the Efficacy of Valganciclovir in Glioblastoma Patients (VIGAS2)

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ClinicalTrials.gov Identifier: NCT04116411
Recruitment Status : Recruiting
First Posted : October 4, 2019
Last Update Posted : October 4, 2019
Sponsor:
Collaborators:
Karolinska University Hospital
Karolinska Institutet
Information provided by (Responsible Party):
Cecilia Soderberg-Naucler, Karolinska Institutet

Brief Summary:
This study is a multicenter randomized double-blinded controlled phase 2 study evaluating the efficacy and safety of the anti-CMV drug valganciclovir vs placebo as add-on therapy in patients with glioblastoma. Valganciclovir is approved for treatment of cytomegalovirus (CMV) infections, but may also have anti-tumoral effects. Current evidence imply that most glioblastomas are CMV positive and that the virus can affect tumor aggressiveness.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Drug: Valganciclovir Tablets Drug: Temozolomide 120 mg Radiation: Radiotherapy 60 Gy Drug: Placebo oral tablet Phase 2

Detailed Description:

Adult patients will either be randomized to standard treatment (temozolomide and radiation therapy) + placebo tablets or to standard treatment + valganciclovir. Patients are randomized using 1 to 1 distribution of the patients between the treatment groups and are stratified according to methylation status of the MGMT promoter; equal proportion of patients are included in each group. A maximum of 30% of patients with methylated MGMT promoter are allowed into the study (to harmonise with current data used for statistical power calculation), as MGMT promotor methylation status is prognostic for patient survival. Patients must enter the study within 10 weeks after surgery.

Full dose treatment with 900mgs of Valganciclovir is given twice daily for 6 weeks, thereafter 900 mgs daily during 98 weeks (total treatment of 24 months). Valganciclovir is available in 450 mg tablets. The dose of Valganciclovir will be adjusted according to renal function.

This study will be performed in compliance with the protocol, ICH-GCP, the declaration of Helsinki and applicable Swedish regulatory requirements.

The study discontinuation criteria are as follows:

  • Withdrawal of consent
  • An adverse event which requires discontinuation of the trial medication or results in
  • inability to continue to comply with trial procedures
  • Disease progression which results in inability to continue to comply with trial
  • procedures
  • Major Protocol deviations
  • Exclusion criteria met

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A multicenter randomized double-blinded controlled phase 2 study evaluating the efficacy of valganciclovir as add-on therapy in glioblastoma patients. Patients will receive either placebo or valganciclovir according to a randomisation list, blinded to the sponsor and study team. Seven centers are aimed to include patients once approval is received for each respective study center.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: VIGAS 2 is conducted under a randomised double blinded protocol. The study team and the patients are blinded to the randomisation list. Randomisation is performed by the contracted Clinical Cancer Center Unit at the Karolinska University Hospital by an unblinded person, Claudia Maes who holds responsibility to select out number codes for coded cans of the study drug. Claudia Maes is unrelated to the sponsor and the study team.
Primary Purpose: Treatment
Official Title: A Multicenter Randomized Double-blinded Controlled Phase 2 Study Evaluating the Efficacy of Valganciclovir as add-on Therapy in Glioblastoma Patients
Actual Study Start Date : September 4, 2019
Estimated Primary Completion Date : August 31, 2024
Estimated Study Completion Date : August 31, 2024


Arm Intervention/treatment
Placebo Comparator: Placebo
Patients will receive placebo tablets with similar appearance as the active drug. Patients receive two 450 mg tablets twice daily taken per orally for 6 weeks, thereafter one 450 mg tablet twice daily for an additional 22.5 months; a total treatment time of 24 months.
Drug: Temozolomide 120 mg
Chemotherapy
Other Names:
  • Temozolomide pill
  • Temozolomide tablet

Radiation: Radiotherapy 60 Gy
Radiation therapy
Other Name: Radiation

Drug: Placebo oral tablet
Placebo treatment of glioblastoma
Other Name: Placebos

Active Comparator: Valganciclovir
Patients will receive valganciclovir tablets with similar appearance as the placebo tablets. Patients receive two 450 mg valganciclovir tablets twice daily taken per orally for 6 weeks, thereafter one 450 mg valganciclovir tablet twice daily for an additional 22.5 months; a total treatment time of 24 months.
Drug: Valganciclovir Tablets
Valganciclovir treatment of glioblastoma
Other Names:
  • Valcyte
  • ValGANcilovir
  • Valganciclovir 450 mg
  • J05AB14
  • Valganciclovir oral

Drug: Temozolomide 120 mg
Chemotherapy
Other Names:
  • Temozolomide pill
  • Temozolomide tablet

Radiation: Radiotherapy 60 Gy
Radiation therapy
Other Name: Radiation




Primary Outcome Measures :
  1. Impact of valganciclovir on median overall survival of glioblastoma patients [ Time Frame: Study closure at 30 months follow up. Survival analyses will be analysed at 12 and 24 months. ]
    Median overall survival will be analyzed using Cox regression analysis and presented by Kaplan-Meier graphs. Proportion of patients alive at 12 or 24 months, respectively, in each study arm and will be analyzed using Fisher exact test.

  2. Baseline and demographic data [ Time Frame: At 30 months follow up ]
    All baseline and demographic data will be analysed using descriptive statistics such as mean, medians, standard deviations etc. for all variables which are continuous. Variables that are categorical will be analysed using frequency tables with number of patients and percent. All these analyses will be divided by treatment group. No formal hypothesis testing will be performed for the demographic and baseline variables.


Secondary Outcome Measures :
  1. Progression free survival at 12 and 24 months [ Time Frame: 12 and 24 months ]

    Tumor recurrence is estimated as clinical and radiological determination (RANO criteria and NANO criteria). The progression free survival will be calculated as the (date of progression - date of first dose of study drug). Patients who are alive without progression at end of follow-up will be censored. Patients who are withdrawn from the study during the follow-up for other reason than dead will be censored at time of withdrawal. Patients who dies for any reason during the follow-up without any progression will be classified as progression using date of death as date of progression. Patients are analysed for stable disease, surgical interventions and treatment failure.

    Progression free survival will be analysed using Cox regression analysis and presented by Kaplan-Meier graphs. The difference in 12 and 24 months progression free survival rates for patients treated with valganciclovir or placebo will be analysed using Fisher exact test.


  2. Incidence of valganciclovir treatment related adverse events [ Time Frame: 30 months follow up time ]
    Number of patients with treatment related adverse events, as assessed by CTCv4. Vital signs: blood pressure (mmHg), heart rate (beats per minute), temperature (degree Celsius), clinical laboratory (total blood counts and differential analyses, liver transaminases and bilirubin, and renal function (creatinine and GFR) and physical exam. Adverse events will be analyzed using a chi-square test without continuity correction.

  3. Health related Quality of Life using EORTC QLQ30 module [ Time Frame: Base line and at every 3 months until 24 months follow up. ]
    Quality of Life measures are recoreded according to EORTC QLQ30 and BN20 module, that are validated for brain tumor patients and measured as a unit of scale. There will be a comparison of scores for patients receiving valganciclovir versus placebo treatment. These are standard tools for assessing patients reported quality of Life along time during treatment. The change from baseline will be analysed using Wilcoxon Rank Sum test.

  4. Cognitive functions [ Time Frame: up to 24 months ]
    MMSE (Mini Mental State Examination) tests are made with a questionary form and will be assesses every three months during the study. The change from baseline will be analysed using Wilcoxon Rank Sum test.

  5. Health related Quality of Life using the EORTC BN20 module [ Time Frame: Base line and at every 3 months until 24 months follow up. ]
    Quality of Life measures are recoreded according to BN20 module, that are validated for brain tumor patients and measured as a unit of scale. There will be a comparison of scores for patients receiving valganciclovir versus placebo treatment. These are standard tools for assessing patients reported quality of Life along time during treatment. The change from baseline will be analysed using Wilcoxon Rank Sum test.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients aged 18 years or older
  2. Patients with newly diagnosed glioblastoma, IDH 1 wt, WHO grade IV
  3. Radical resection
  4. Concomitant treatment with temozolomide and radiation therapy
  5. MGMT promoter methylation status
  6. Patients with at least KPS 70 , ECOG/WHO 2
  7. Patients providing written informed consent
  8. Patients cooperative and able to complete all the assessment procedures.
  9. Females of child-bearing age must have a negative pregnancy test at screening (all premenopausal women, or in case when menstrual status can not be ascertained in women under the age of 55). Female patient must agree to utilize a highly efficient birth control method throughout the study period (Pearl index <1, e.g: oral contraception with gestagens, transdermal contraceptives, implants, injectables, intrauterine devices, bilateral tubal occlusion, sexual abstinence or vasectomised partner). The birth control method must be used at least 30 days after treatment end. Pregnancy testing should be performed at monthly intervals due to high teratogenic potential of valganciclovir. Men are recommended to use condoms with female partners during, and for at least 90 days following treatment with Valganciclovir.
  10. Patients must be enrolled within 10 weeks after surgery

Exclusion Criteria:

  1. Patients allergic to, or who do not tolerate Valganciclovir, aciclovir or valaciclovir treatment
  2. Patients with decreased cognitive function (below 24 in MMSE test)
  3. Pregnant or lactating females
  4. Patients not signing informed consent
  5. Patient is simultaneously participating in another experimental drug therapy trial
  6. Neutrophil count < 1,5 cells/ 109/L
  7. Platelet count < 150 cells/ 109/L
  8. HGB < 80 g/L
  9. Abnormal renal function (GFR < 30)
  10. Secondary glioblastoma, or glioblastoma IDH1 mutated.
  11. Unfit for any other reason judged by investigator

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04116411


Contacts
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Contact: Cecilia Soderberg-Naucler, MD, PhD +46702427471 cecilia.naucler@ki.se
Contact: Afsar Rahbar, PhD +46769496980 afsar.rahbar@ki.se

Locations
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Sweden
SE01 Karolinska University Hospital Recruiting
Solna, Stockholm, Sweden, SE17164
Contact: Giuseppe Stragliotto, MD, PhD    +46723161644    giuseppe.stragliotto@sll.se   
Contact: Eva Hamberg, Nurse    +46-708776885    eva.hamberg@sll.se   
Principal Investigator: Giuseppe Stragliotto, MD, PhD         
Sponsors and Collaborators
Cecilia Soderberg-Naucler
Karolinska University Hospital
Karolinska Institutet
Investigators
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Principal Investigator: Giuseppe Stragliotto, MD, PhD Karolinska University Hospital

Publications of Results:
Other Publications:
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Responsible Party: Cecilia Soderberg-Naucler, Professor, Karolinska Institutet
ClinicalTrials.gov Identifier: NCT04116411     History of Changes
Other Study ID Numbers: Eudra CT: 2019-001083-30
First Posted: October 4, 2019    Key Record Dates
Last Update Posted: October 4, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: When approval from authorities in Sweden allows data sharing, these will be available for other researchers.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: When data is available and permissions to share these are approved, data will be available for other researchers.
Access Criteria: Access will be given by the sponsor upon request.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Cecilia Soderberg-Naucler, Karolinska Institutet:
cytomegalovirus
valganciclovir
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Valganciclovir
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents